There have been major advances in the prevention of mother-to-child transmission (PMTCT) of HIV in developed countries, but hundreds of thousands of children are newly infected with HIV every year in sub- Saharan Africa. Initiation of antiretroviral therapy (ART) in eligible pregnant women (CD4<350 cells/uL) can play a critical role in PMTCT efforts, as women who are eligible for ART are most likely to transmit HIV to their children and also are at the greatest risk of morbidity and mortality themselves. However it is clear that current approaches and services for ART initiation in pregnancy are suboptimal in South Africa (SA) and other parts of the continent where PEPFAR is active. Many eligible women do not start ART while pregnant, and those who do often begin too late in pregnancy to realize the full benefits. We propose to evaluate a new intervention to promote rapid ART initiation among eligible pregnant women in Cape Town, SA. The Emnonophele Intervention (meaning taking care of health in isiXhosa, the local language) represents a new operational paradigm for fast tracking ART initiation in pregnancy that combines strategies to address the key health systems, clinical, and patient education and adherence issues that currently act as barriers to rapid ART initiation in pregnancy. The intervention features midwife-delivered ART within the antenatal clinic (ANC); using an efavirenz-containing regimen that avoids the delays and toxicities associated with nevirapine; and adapting patient education to be delivered during and immediately after (rather than before) ART initiation. Our team consists of leading researchers in PMTCT, ART and patient education working in partnership with local PEPFAR and public health care services. Pilot work on EI has demonstrated its feasibility and acceptability among HIV-infected pregnant women and health care providers. We propose a pragmatic trial to provide a rigorous evaluation of EI versus the existing standard of care, with HIV viral suppression at the time of delivery as the primary outcome. Secondary aims include the transmission of HIV from mother-to-child and retention in care through 6 months postpartum, as well as the acceptability and cost-effectiveness of this intervention. By recognizing that ART-eligible pregnant women are a vulnerable, high risk group EI shifts the paradigm for implementation of PMTCT and ART services, and addresses well-documented challenges to delivering ART in pregnancy to optimize both maternal and child health outcomes. We propose a rigorous evaluation of the feasibility, implementation, impact and cost-effectiveness of EI. Developed in partnership with SA DOH and local services, EI has the potential to strengthen PEPFAR-supported PMTCT and HIV treatment services locally and nationally. Furthermore, EI will provide a feasible and evidence-based intervention platform to enhance ART use during pregnancy, contributing directly to efforts to eliminate new pediatric HIV infections in Africa. PUBLIC HEALTH RELEVANCE: Using antiretroviral therapy (ART) effectively in pregnancy is a critical part of efforts to reduce the mother-to- child transmission of HIV infection in South Africa and many other countries where PEPFAR is active. However we know there are many problems facing current services to start pregnant women on ART and follow them during pregnancy, so we propose an innovative new approach for ART initiation in pregnancy that emphasizes ART-eligible pregnant women as a high-risk population who need special attention. We will study a new model to revolutionize ART initiation in pregnancy and will make a major contribution to improving maternal and child health in countries like South Africa where HIV is common.